No abstract

Rationale: Autophagy, a bulk degradation process of cytosolic proteins and organelles, is protective during nutrient starvation in cardiomyocytes (CMs). However, the underlying signaling mechanism mediating autophagy is not well understood. Objective:We investigated the role of FoxOs and its posttranslational modification in mediating starvationinduced autophagy. Methods and Results:Glucose deprivation (GD) increased autophagic flux in cultured CMs, as evidenced by increased mRFP-GFP-LC3 puncta and decreases in p62, which was accompanied by upregulation of Sirt1 and FoxO1. Overexpression of either Sirt1 or FoxO1 was sufficient for inducing autophagic flux, whereas both Sirt1 and FoxO1 were required for GD-induced autophagy. GD increased deacetylation of FoxO1, and Sirt1 was required for GD-induced deacetylation of FoxO1. Overexpression of FoxO1(3A/LXXAA), which cannot interact with Sirt1, or p300, a histone acetylase, increased acetylation of FoxO1 and inhibited GD-induced autophagy. FoxO1 increased expression of Rab7, a small GTP-binding protein that mediates late autophagosome-lysosome fusion, which was both necessary and sufficient for mediating FoxO1-induced increases in autophagic flux. Although cardiac function was maintained in control mice after 48 hours of food starvation, it was significantly deteriorated in mice with cardiac-specific overexpression of FoxO1(3A/LXXAA), those with cardiac-specific homozygous deletion of FoxO1 (c-FoxO1 Key Words: autophagy Ⅲ starvation Ⅲ FoxO Ⅲ Sirt1 Ⅲ Rab7 Ⅲ deacetylation M acroautophagy (termed hereafter as autophagy) is a dynamic process of intracellular bulk degradation in which cytosolic proteins and organelles are sequestered into double-membrane vesicles called autophagosomes to be fused with lysosomes for degradation. 1 In the heart, autophagy maintains protein quality control, adapts to nutrient and oxygen deprivation during myocardial ischemia, and mediates cell death during reperfusion injury. 2,3 Autophagy during nutrient deprivation is an adaptive mechanism that allows the cells to survive by degrading the intracellular protein and lipid cargo and recycling the amino and fatty acids to generate ATP. 2 The nutrient status has a profound effect on cardiac contractility, and activation of autophagy during starvation is protective for the heart. The intracellular signaling mechanism by which nutrient starvation activates autophagy in cardiomyocytes (CMs) is not well understood, however.The forkhead box, class O (FoxO) family of transcription factors are present as 4 distinct isoforms (FoxO1, FoxO3, FoxO4, and FoxO6) in mammals. FoxO proteins play an important role in several intracellular functions, such as metabolism, stress resistance, longevity, tumor suppression, and cell size regulation. 4 The key to the myriad functions of FoxO proteins lies in the complex posttranslational modifications they undergo. They are phosphorylated in response to insulin and growth factors, dephosphorylated by protein phosphatases, ubiquitinated in response to oxidative stre...

Editorial, see p 225Mitochondria are dynamic organelles that constantly undergo fusion and fission 5 to adapt to changes in the cellular environment. Although mitochondrial fusion allows mitochondria to maintain membrane potential by fusing depolarized mitochondria to intact ones, fission allows the segregation of unrecoverable mitochondria so that they can be eliminated by autophagy or mitophagy, a specialized form of autophagy.6 Mitochondrial fusion is critically